Huntington's disease is a progressive neurodegenerative disease for which no effective treatment exists. Transcriptional dysregulation is now considered to be an important mechanism in the pathogenesis of Huntington's disease (HD) and other polyglutamine diseases. Alteration of mRNA populations, including those encoding for neurotransmitter receptors, is a hallmark of murine and cellular models of HD as well as human HD. Although numerous studies have confirmed that mRNA populations are altered in HD models, the mechanism underlying such changes remains unknown. Transcription factors, including specificity protein 1 (Sp1), have been implicated in HD pathogenesis, but the role of altered Sp1 function in producing mRNA alterations has not been answered. In this application, we take advantage of a well-described set of gene alterations--those occurring in neurotransmitter receptors--as a starting point for determining the molecular mechanisms of transcriptional dysregulation. We propose a series of hypotheses that will yield critical mechanistic insight into the processes that alter mRNA populations and cause disease pathogenesis. Specific Aim 1 will test the hypothesis that mutant huntingtin selectively alters the association of Sp1 with the promoters of genes that are downregulated in HD. Chromatin Immunoprecipitation (CHIP) assays will assess the degree of Sp1-gene binding in cellular, murine and human HD tissues. Specific Aim 2 will test the hypothesis that decreased Sp1 binding to selected gene promoters causes HD phenotypes. Sp1 levels will be manipulated through RNA interference, dominant negative constructs and overexpression, and the effects of these manipulations on mRNA and cellular toxicity will be assessed. Specific Aim 3 tests the hypothesis that interference in Sp 1 function by huntingtin causes abnormal histone modification. Histone modifications will be examined in mouse and cell models of HD. Taken together, these proposed experiments will systematically address several key molecular loci of potential damage by mutant huntingtin. Such fundamental mechanistic information is critical to the eventual development of effective therapy for HD.